Anti-cldn18.2 antibody, and pharmaceutical composition and use thereof

Abstract

Provided are an anti-CLDN18.2 antibody, and a pharmaceutical composition and the use thereof. Specifically, provided is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof. The anti-CLDN18.2 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises HCDR1 to HCDR3, and the light chain variable region comprises LCDR1 to LCDR3, wherein the amino acid sequence of HCDR1 is as shown in SEQ ID NO: 5, the amino acid sequence of HCDR2 is as shown in SEQ ID NO: 6, and the amino acid sequence of HCDR3 is as shown in SEQ ID NO: 7; and the amino acid sequence of LCDR1 is as shown in SEQ ID NO: 8, the amino acid sequence of LCDR2 is as shown in SEQ ID NO: 9, and the amino acid sequence of LCDR3 is as shown in SEQ ID NO: 10. The anti-CLDN18.2 antibody has a good biological activity and anti-tumor application prospects.

1 . An anti-CLDN18.2 antibody or an antigen-binding fragment thereof, wherein the anti-CLDN18.2 antibody comprises a heavy chain variable region comprising HCDR1 to HCDR3 and a light chain variable region comprising LCDR1 to LCDR3, wherein:
 an amino acid sequence of HCDRI is set forth in SEQ ID NO: 5, an amino acid sequence of HCDR2 is set forth in SEQ ID NO: 6, and an amino acid sequence of HCDR3 is set forth in SEQ ID NO: 7, and   an amino acid sequence of LCDR1 is set forth in SEQ ID NO: 8, an amino acid sequence of LCDR2 is set forth in SEQ ID NO: 9, and an amino acid sequence of LCDR3 is set forth in SEQ ID NO: 10.   
     
     
         2 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein,
 an amino acid sequence of the heavy chain variable region of the anti-CLDN18.2 antibody is selected from SEQ ID NO: 2, SEQ ID NO: 11, SEQ ID NO: 13, and SEQ ID NO: 15; and   an amino acid sequence of the light chain variable region of the anti-CLDN18.2 antibody is selected from SEQ ID NO: 4, SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 21.   
     
     
         3 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein,
 the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 2, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 4;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 11, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 17;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 11, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 19;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 11, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 21;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 13, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 17;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 13, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 19;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 13, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 21;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 17;   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 19; or   the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 21.   
     
     
         4 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein for the antibody, a heavy chain constant region is an Ig gamma-1 chain C region or an Ig gamma-4 chain C region, and a light chain constant region is an Ig kappa chain C region. 
     
     
         5 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein the anti-CLDN18.2 antibody or the antigen-binding fragment thereof is selected from Fab, Fab′, F (ab′) 2 , Fd, Fv, dAb, a complementarity determining region fragment, a single chain fragment variable, a humanized antibody, or a chimeric antibody. 
     
     
         6 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein,
 the antibody comprises a non-CDR region derived from a non-murine species, such as from a human antibody.   
     
     
         7 . The anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein:
 an EC50 for binding of the anti-CLDN18.2 antibody to a cell expressing CLDN18.2 is less than or equal to 0.5 μg/mL, less than or equal to 0.4 μg/mL, or less than or equal to 0.3μg/mL;   preferably, the EC50 is measured by FACS.   
     
     
         8 . The antibody or the antigen-binding fragment thereof according to  claim 1 , wherein the antibody is a monoclonal antibody produced by a hybridoma cell line LT020 deposited at China Center for Type Culture Collection (CCTCC) with a CCTCC designation of CCTCC NO. C2022124. 
     
     
         9 . An isolated nucleic acid molecule encoding the anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 . 
     
     
         10 . A recombinant vector, comprising the isolated nucleic acid molecule according to  claim 9 . 
     
     
         11 . A host cell, comprising the isolated nucleic acid molecule according to  claim 9  or comprising a recombinant vector, wherein the recombinant vector comprises the isolated nucleic acid molecule according to  claim 9 . 
     
     
         12 . A hybridoma cell line LT020 deposited at China Center for Type Culture Collection (CCTCC) with a CCTCC designation of CCTCC NO. C2022124. 
     
     
         13 . An antibody-drug conjugate, comprising an antibody or an antigen-binding fragment thereof and a small molecule drug, wherein the antibody or the antigen-binding fragment thereof is the anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 ; preferably, the small molecule drug is a small molecule cytotoxic drug; more preferably, the small molecule drug is an anti-tumor chemotherapeutic drug. 
     
     
         14 . The antibody-drug conjugate according to  claim 13 , wherein the antibody or the antigen-binding fragment thereof is linked to the small molecule drug via a linker; for example, the linker is a hydrazone bond, a disulfide bond, or a peptide bond;
 preferably, a molar ratio of the antibody or the antigen-binding fragment thereof to the small molecule drug is 1:(2-4).   
     
     
         15 . A pharmaceutical composition, comprising an effective amount of the anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable auxiliary materials. 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . A method for treating or preventing a tumor, comprising the step of administering to a subject in need thereof an effective amount of the anti-CLDN18.2 antibody or the antigen-binding fragment thereof according to  claim 1 , wherein,
 preferably, the tumor is a CLDN18.2-positive tumor;   preferably, the tumor is one or more selected from biliary tract cancer, bronchogenic carcinoma, lymphoma, ovarian cancer, esophageal cancer, melanoma, a hematological malignancy, glioblastoma, lung cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, liver cancer, gastric cancer, breast cancer, brain cancer, pancreatic cancer, thyroid cancer, head and neck cancer, and kidney cancer.   
     
     
         19 . The method for treating or preventing a tumor according to  claim 18 , wherein drug administration is performed before or after surgery and/or before or after radiotherapy. 
     
     
         20 . The method for treating or preventing a tumor according to  claim 18 , wherein,
 a dose for each administration of the anti-CLDN18.2 antibody or the antigen-binding fragment thereof is 0.1-100 mg per kg body weight, preferably 5-50 mg or 5-15 mg per kg body weight;   preferably, drug administration is performed once every 3 days, every 4 days, every 5 days, every 6 days, every 10 days, every 1 week, every 2 weeks, or every 3 weeks;   preferably, a route of administration is intravenous drip infusion or intravenous injection.